3-{5-[4-(cyclopentyloxy)-2-hydroxybenzoyl]-2-[(3-hydroxy-1,2-benzisoxazol-6-yl)methoxy]phenyl}propionic acid (henceforth referred as T-5224) or a salt thereof is a compound in development as a therapeutic agent for inflammatory diseases targeting transcription factor AP-1 (Patent Document 1).
T-5224 is a hardly-soluble medication with low solubility in the secretions inside the gastrointestinal tract (in the range from acidic to neutral). As a result, when solid T-5224 is administered orally, the absorption from the gastrointestinal tract is not adequate. In addition, when a basic solution of T-5224 is administered orally, due to the change of solution property by secretion inside the gastrointestinal tract, T-5224 precipitates, and an adequate absorption is not achieved.
For improving the solubility of hardly-soluble medications, various pharmaceutical technologies have been studied. For example, (1) a method for improving the solubility by making a salt of the hardly-soluble medication, (2) a method for making amorphous, (3) a method for making soluble by forming a cyclodextrin clathrate (4) a method for making soluble by adding a surface active agent (5) a method for dissolving in a solvent with affinity for the hardly-soluble medication (for example, Macrogol and propylene glycol, and the like) (6) a method for making fine particles (Non-Patent Document 1).
However, (1) due to the change of solution property by secretion inside the gastrointestinal tract, the salt of T-5224 precipitates; (2) with a method for making soluble by adding a surface active agent, damage to the gastrointestinal tract due to the surface active agent is a concern; (3) with regard to the method for making amorphous, a method for making a cyclodextrin clathrate, and a method for making fine particles, these require special manufacturing devices and complex processes, and manufacture is not easy; (4) with regard to a method for dissolving in solvents that have affinity with the hardly-soluble medications, there is concern that there may be side-effects from the solvents, and furthermore for making soft gelatins and the like, a special manufacturing device and complex processes become necessary, and the manufacturing is not easy.
Formulations of T-5224 or a salt thereof that have good absorption through oral administration and that can be produced easily are not known.
Patent Document 1: International Publication 03/042150 pamphlet
Non-Patent Document 1: Edited by The Society of Powder Technology, Japan/Division of Particulate Design and Preparations “Particle Design and Pharmaceutical Technology that are useful now” First edition, Jiho, Inc., Sep. 1, 2003, p. 205-211.